Clinical decision thresholds for surfactant administration in preterm infants: a systematic review and network meta-analysis

Summary Background The ideal threshold at which surfactant administration in preterm neonates with respiratory distress syndrome (RDS) is most beneficial is contentious. The aim of this systematic review was to determine the optimal clinical criteria to guide surfactant administration in preterm neonates with RDS. Methods The systematic review was registered in PROSPERO (CRD42022309433). Medline, Embase, CENTRAL and CINAHL were searched from inception till 16th May 2023. Only randomized controlled trials (RCTs) were included. A Bayesian random effects network meta-analysis (NMA) evaluating 33 interventions was performed. The primary outcome was requirement of invasive mechanical ventilation (IMV) within 7 days of life. Findings 58 RCTs were included. In preterm neonates ≤30 weeks after adjusting for the confounding factor of modality of surfactant administration, an arterial alveolar oxygen tension ratio (aAO2) <0.36 (FiO2: 37–55%) was ranked the best threshold for decreasing the risk of IMV, very low certainty. Further, surfactant administration at an FiO2 40–45% possibly decreased mortality compared to rescue treatment when respiratory failure was diagnosed, certainty very low. The reasonable inference that could be drawn from these findings is that surfactant administration may be considered in preterm neonates of ≤30 weeks’ with RDS requiring an FiO2 ≥ 40%. There was insufficient evidence for the comparison of FiO2 thresholds: 30% vs. 40%. The evidence was sparse for surfactant administration guided by lung ultrasound. For the sub-group >30 weeks, nebulized surfactant administration at an FiO2 < 30% possibly increased the risk of IMV compared to Intubate-Surfactant-Extubate at FiO2 < 30% and 40%, and less invasive surfactant administration at FiO2 40%, certainty very low. Interpretation Surfactant administration may be considered in preterm neonates of ≤30 weeks’ with RDS if the FiO2 requirement is ≥40%. Future trials are required comparing lower FiO2 thresholds of 30% vs. 40% and that guided by lung ultrasound. Funding None.


Introduction
Surfactant administration for the treatment of respiratory distress syndrome (RDS) is the mainstay intervention to reduce mortality and major morbidity in preterm neonates. 1 Since the first clinical trial performed in 1980, significant progress has been made with respect to its use. 2 Systematic reviews indicate that early surfactant administration and the use of lesser invasive modalities such as less invasive surfactant administration (LISA) reduce mortality and the risk of bronchopulmonary dysplasia (BPD). However, there is a paucity of evidence to define the optimal thresholds at which exogenous surfactant therapy would be most effective. 1,[3][4][5] Our current understanding is that the pathophysiology of RDS is multifactorial, of which surfactant deficiency remains the most important aspect. 6 In the absence of a clinically feasible test to accurately and timely quantify surfactant levels in the preterm lung, several other markers have been used to classify the severity of RDS. Of these, the fraction of inspired oxygen (FiO 2 ) requirement is most used. To date, there are no randomized controlled trials (RCT) evaluating different FiO 2 thresholds together with defined modalities of surfactant administration in preterm neonates with RDS who are stabilized on CPAP. 7,8 This lacuna is evident in the differing recommendations by various international RDS treatment guidelines, focusing predominantly on oxygen requirement to maintain acceptable peripheral saturations (SpO 2 ). 3,9 However, apart from FiO 2 there may be other parameters available to predict significant RDS and guide targeted surfactant administration, ideally during an optimal time frame.

Research in context
Evidence before this study A literature search of the databases Medline and Embase using the key words 'surfactant', 'respiratory distress syndrome' and 'preterm' was performed from 1st January 2000 to 16th May 2023. Only systematic reviews and randomized controlled trials which had evaluated surfactant administration in preterm infants were included. Studies published in both English and non-English languages were eligible for inclusion and descriptive reviews were excluded. Three network meta-analyses (NMAs) related to surfactant administration in preterm neonates with RDS were identified. One NMA which focussed on various non-invasive respiratory support modalities in preterm infants such as CPAP, noninvasive positive pressure ventilation along with different surfactant administration modalities such as INSURE, LISA and through LMA reported that LISA was associated with the lowest likelihood of mortality or BPD at 36 weeks' postmenstrual age (OR, 0.49; 95% CrI, 0.30-0.79), with the evidence quality being low. The other NMA exclusively evaluated the various modalities of surfactant administration in preterm infants and found that surfactant administration via thin catheters was associated with lower likelihood of mortality (OR, 0.64; 95% CI, 0.54-0.76), need for mechanical ventilation (OR, 0.43; 95% CI, 0.29-0.63) and bronchopulmonary dysplasia (OR, 0.57; 95% CI, 0. 44-0.73) with the evidence quality being moderate. The most recently published NMA studied the different FiO 2 thresholds for surfactant administration in preterm neonates of less than 32 weeks' gestation with RDS and found that there was no clear benefit of surfactant therapy based on different FiO 2 cut-off levels with the quality of evidence being low.

Added value of this study
This NMA investigated the various thresholds utilized for surfactant administration. It provides a holistic approach of evaluating surfactant administration in preterm neonates with RDS by studying a range of techniques, thresholds including but not merely focussing on FiO 2 alone, and respiratory support modes. By including the technique of surfactant administration as a part of intervention we are cautiously confident to have circumvented the risk of intransitivity, which is the fundamental assumption of an NMA analysis. This novel approach of combining the two important aspects related to surfactant administration has not been utilized in the previously published NMAs. The interpretation of the results of this NMA paves way for clinically relevant conclusions and henceforth should help guide safe clinical practice.

Implications of all the available evidence
The ideal threshold for surfactant administration in preterm neonates with RDS may not be restricted to the FiO 2 requirement alone but may also be related to other criteria such as a/AO 2 ratio, clinical assessment of respiratory distress, severity of RDS as adjudged by lung ultrasound and lamellar body counts. Based on the results of this NMA, in preterm neonates of ≤30 weeks' gestation, surfactant administration may be considered when an FiO 2 threshold of 40% is reached. Clinicians may take into consideration many of the other aforementioned parameters while adjudging the requirement of surfactant replacement therapy in preterm neonates with RDS as well. Such an approach might identify preterm neonates with RDS who could benefit from surfactant administration earlier and hence improve clinical outcomes. Finally, this systematic review also identifies gaps in current literature to stimulate discussion and advise future research into interventions for which the evidence certainty is very low to low, such as surfactant guided by lung ultrasound severity scores.

Articles
Other parameters for predicting the severity of RDS that have been studied include arterial alveolar oxygen tension ratio (a/AO 2 ), lamellar body counts in lung-or gastric aspirates, lung ultrasound and clinical scoring systems of respiratory distress. 8,[10][11][12] This systematic review was performed with an aim to assess the different thresholds for surfactant administration in preterm neonates (≤36 weeks') diagnosed with or at risk of RDS. A network meta-analysis (NMA) was used to synthesize data as it allows for comparing efficacies as well as ranking these through the provision of indirect evidence as there are only a few RCTs comparing the various decision thresholds for surfactant administration. 13

Methods
The systematic review was registered in PROSPERO (CRD42022309433). 14 The results of the NMA was reported according to PRISMA-NMA. 15

Search strategy
Medline, Embase, CENTRAL and CINAHL were searched by two authors independently without any restrictions 16 (eTable S1). A balance of recall and precision was maintained while searching all the databases. The PRISMA flowchart is given in Fig. 1.

Selection criteria Patient population
Preterm neonates (born at ≤36 weeks' gestation) and diagnosed with or at risk of RDS.

Interventions/comparators
33 interventions were evaluated. Each intervention included two components: The threshold used for surfactant administration and the modality by which surfactant was administered (Annexure 1). The modality of surfactant administration was combined along with the treatment threshold to avoid confounding and intransitivity.

Outcomes
The primary outcome was requirement of invasive mechanical ventilation (IMV) within the first week of life. The secondary outcomes included mortality before discharge, mortality or BPD (oxygen requirement at 36 weeks' postmenstrual age), intraventricular hemorrhage grade (IVH) > grade 2, 17 air leak, receipt of multiple doses of surfactant and long term neurodevelopmental outcomes.

Study selection
Only RCTs were included.

Time frame
The databases were searched from inception until 16th May 2023.

Risk of bias assessment
The risk of bias of the included studies was evaluated using the Cochrane risk of bias tool version 2.0 by two authors independently. 18 Disagreements were resolved by consensus.

Certainty of evidence (CoE)
CoE for the NMA effect estimates was assessed according to GRADE recommendations. 19 The CoE is classified into 4 categories: very low, low, moderate and high. Whilst very low and low CoE indicate that the true effect probably or might be different from the estimated effect, moderate CoE suggest that the true effect is probably close to the estimated effect. High CoE means that the authors are very confident that the true effect is similar to the estimated effect.

Statistical analysis
A Bayesian NMA was performed using the R-software (R Foundation for Statistical Computing, Vienna, Austria) and the "gemtc" package was utilized for data synthesis. 20 The "netmeta" package was utilized for pairwise meta-analysis. 20 Markov chain Monte Carlo (MCMC) simulation using vague priors with four chains, burn-in of 50,000 iterations, followed by 10,00,000 iterations and 10,000 adaptations was used. Model convergence was assessed using Gelman-Rubin Potential Scale Reduction Factor, trace and density plots. Leverage plots, total residual deviance and deviance information criterion were evaluated to confirm model convergence. Intransitivity was evaluated by comparing the characteristics of the included the studies and inconsistency by node splitting. Pair-wise meta-analysis of RCTs was also performed. The effect estimates of the NMA were reported as risk ratio (RR) with 95% credible interval (CrI). The NMA estimates were illustrated with forest plots and matrix plots. Surface under the cumulative ranking curve (SUCRA) was used to depict the ranking of the interventions. 21 Publication bias in direct evidence from meta-analyses of RCTs would be assessed if at least 10 trials had evaluated an outcome. When the data from the trials could not be synthesized in an NMA, they were described in the narrative review.

Sub-group analyses/meta-regression
Sub-groups analyses were performed based on gestational age: ≤30 weeks and >30 weeks. Meta-regression was done for the following gestational ages: 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, and 36 weeks.

Role of funding source
There was no funding obtained for this study. All the authors of this paper namely, Viraraghavan Vadakkencherry Ramaswamy, Tapas Bandyopadhyay, Thangaraj Abiramalatha, Abdul Kareem Pullattayil, Tomasz Szczapa, Clyde J. Wright and Charles Christoph Roehr have access to the data set and all of them had made the decision to submit for publication.

Outcomes
Primary outcome: requirement of IMV non-invasive respiratory support; pCO 2 /PaCO 2 , partial pressure of carbon dioxide in the blood; PaO 2 , partial pressure of oxygen in the blood; PAO 2 , partial pressure of alveolar oxygen; PDA, patent ductus arteriosus; PDI, psychomotor developmental index; PIP, peak inspiratory pressure; PEEP, post end expiratory pressure; PMA, post menstrual age; PIE, pulmonary interstitial emphysema; PPV, positive pressure ventilation; RDS, respiratory distress syndrome; rScO 2 , cerebral oxygen saturation; SpO 2 , oxygen saturation as measured by pulse oximetry; SBP, systolic blood pressure; ROP, retinopathy of prematurity; tcPO 2 , transcutaneously monitored PaO 2 ; USG, ultrasonography; w, weeks.  Fig. 2. The matrix plot depicting the NMA effect estimates for all the comparisons is given in Table 2. The CoE for NMA effect estimates for all the comparisons is given in Table 3. The forest plot of pairwise comparisons of RCTs is provided in eFigure S1. Inconsistency assessment for this subgroup was not  surfactant administration when respiratory failure is diagnosed followed by continued mechanical ventilation; MVRESCUE_LATE, surfactant administration on mechanical ventilation when a particular mean airway pressure or FiO 2 threshold is reached; MVF, surfactant administration when a particular FiO 2 threshold is reached followed by continued mechanical ventilation. The effect estimates expressed in bold fonts were statistically significant with the 95% CI not crossing the line of no effect. possible due to the sparseness of the network. When Inconsistency was assessed for neonates of all gestations, it was not detected (eFigure S2).
Metaregression. While none of the comparisons showed statistically significant differences for the outcome of IMV in preterm neonates of gestation 24 weeks and 28 weeks, the results were similar to that of the primary analysis at 30 weeks' gestation (eFigure S3).
Neonates >30 weeks. There were two subnetworks for the outcome of IMV.   (MVF40_45), surfactant administration when respiratory failure was diagnosed followed by continued mechanical ventilation (MVRESCUE) (Fig. 3
Metaregression. The findings were similar to the primary analysis at different gestational ages (eFigure S11).

Mortality or BPD
NMA was done including all preterm neonates as the network was sparse and sub-group analysis based on gestational age was not feasible. No statistically significant differences were found between any of the comparisons (eFigures S14 and S15, eTables S15-S17). Inconsistency assessment and metaregression was not feasible due to the sparseness of the network.

IVH grade >2
Neonates ≤30 weeks 15 interventions which included 25 studies and 6054 neonates were analyzed in the NMA. No statistically significant differences were found between any of the comparisons for this outcome (eFigures S16 and S17, eTables S18-S20).
Metaregression. The results of the NMA were similar to that of the primary analysis at different gestational ages (eFigure S18).

Neonates >30 weeks
Likewise for the other sub-group of preterm neonates, there were no statistically significant differences between any of the comparisons (eFigures S19 and S20, eTables S21-S23).

Air leak
Similar to the outcome of mortality or BPD, NMA was performed for air leak including preterm neonates of all gestational ages (eFigure S21). Multiple interventions possibly resulted in lesser risk of air leak when compared to others. SUCRA rated the following interventions as the most efficacious: INSUR-ELAMCOUNT (0.91), INSUREaAO 2 less0_36 (0.89), INSUREF22_30 (0.86) and NEBF22_30 (0.75). Inconsistency was detected in the network for which CoE for the NMA effect estimate was rated down by one level (eFigures S22 and S23, eTables S24-S26).

Metaregression
Whilst at gestational age of 32 weeks the results were similar to that of the primary analysis, at 28 weeks and 36 weeks, INSURECLINICALRD decreased the risk of air leak when compared to MVRESCUE_LATE (eFigure S24).

Discussion
This systematic review and NMA synthesized data from 53 studies. Since there were only a few RCTs that had compared the various thresholds, the network estimates were predominantly derived from indirect evidence. Further, the results were analyzed separately wherever feasible for two sub-groups of preterm neonates with a gestational age cut-off of 30 weeks to avoid intransitivity as the incidence of the outcomes analyzed might be different in these sub-groups.
Our overall interpretation of the results indicates that when adjusted for the modality of surfactant administration (e.g., LISA, INSURE), an aAO 2 of <0.36 was associated with decreased risk of IMV compared to various other thresholds in preterm neonates of ≤30 weeks' gestation with RDS. An aAO 2 of 0.36 corresponds to an FiO 2 of 37-55%. Similarly, an FiO 2 of 40-45% was associated with lesser risk of mortality when compared to a higher FiO 2 in this sub-group of preterm neonates. Further, evaluation of different modalities of surfactant suggested that less invasive modalities of surfactant administration at various thresholds except for nebulized surfactant administration was associated with decreased risk of IMV when compared to surfactant administration via endotracheal tube followed by continued mechanical ventilation for preterm neonates with RDS.
The recent Cochrane review had suggested that LISA when compared to INSURE resulted in lesser risk of risk of death or BPD, need for assisted breathing in the first 72 hours of life, severe brain bleeding, death during first hospitalisation, and BPD among survivors, the results being different from that of ours'. 77 The difference in results between the findings of our NMA and the Cochrane review could be attributed to many reasons. Firstly, the literature search in the Cochrane review was until September 2020 and the largest RCT published till date was not included. 28 Secondly, the study population and the threshold for surfactant administration varied between the studies included in the Cochrane review. Thirdly, sub-group analyses based on gestational age was not performed due to lack of data. Finally, since ours' was an NMA and the Cochrane meta-analysis was a pairwise one, the addition of indirect evidence in the NMA in addition to the direct evidence from pairwise meta-analysis would have modified the effect estimates.
Amongst the neonates born at ≤30 weeks, SUCRA ranked aAO 2 < 0.36 was ranked as the best intervention. However, irrespective of the less invasive modality utilized (INSURE or LISA), clinical benefit or harm could not be ruled out for FiO 2 of 30% vs. 40%. Since these levels have been widely studied and have been recommended as thresholds for surfactant administration, we suggest future trials comparing them. 78 We acknowledge that in times where peripheral oxygen saturation measurement via pulse-oximetry is widely available, arterial blood gas analysis is not as frequently performed and clinical teams are not universally confident in interpreting aAO 2 data from these. Therefore, future studies are needed to link FiO 2 and aAO 2 in the context of establishing the surfactant need. Choosing a threshold higher than these might not be appropriate as obliquely indicated by the comparison INSURE at aAO 2 < 0.36 vs. INSURE as a rescue measure where the former was possibly shown to be beneficial. Metaregression indicated that in neonates born at threshold of viability such as at 24 weeks, clinical benefit or harm could not be ruled out for either the various thresholds or the mode of surfactant administration. In a survey conducted by International Network for Evaluating Outcomes (iNEO), it was reported that most of the countries preferred the invasive approach of continuing IMV in neonates born at 23-24 weeks. 79 Since improving the intact survival of neonates born at threshold of viability is a major focus of neonatal medicine as of present, future trials are warranted in this sub-group of preterm neonates as well. 80 Earlier surfactant administration, as informed by LUS may warrant further investigation. Though promising, at present, trials have not shown LUS to have additional benefits over FiO 2 in evaluating the severity of RDS and surfactant need. 11,81 Though SUCRA was used to rank the various interventions across outcomes, it has some limitations. SUCRA values can vary across outcomes for the same regimen, the differences might be due to chance alone as it does not account for the 95% CI, and they do not capture the magnitude of differences in effects between interventions.
Further, surfactant administration through LISA-CLINICALRD was shown to decrease mortality when compared to the use of only CPAP. This finding might be of relevance in resource limited settings where blended oxygen is not available, and the clinicians must depend upon clinical respiratory distress scoring. Though such scores have been developed, surfactant availability and training of health care personnel might be bottle necks. 12 For the other secondary outcomes of air leak and receipt of repeated doses of surfactant, NMA indicated that earlier surfactant administration at FiO 2 of 22-30%, aAO 2 < 0.36 and that guided by lamellar body counts might possibly be beneficial.
Our NMA indicated that the recently evaluated strategy of strategy Intubate-Recruit-Surfactant-Extubate was not superior to the traditionally used INSURE technique. Two trials evaluating INRECSURE were included in the NMA. 67,70 It is to be noted that the trial by Vento et al. which had utilized high frequency oscillation ventilation (HFOV) for recruitment had shown a decreased risk of IMV in extremely low gestational age group neonates (ELGANs). 67 The probable reason for the discrepancy between our results and that of the trial might be attributed to the addition of indirect evidence in the NMA analysis. Also, the possibility of intransitivity could not be ruled out as Vento et al. had exclusively evaluated ELGANs who were sicker compared to those infants included in the other trials. Further, the patient population and the recruitment technique utilized by these two trials were different. Whilst Vento et al. had utilized HFOV for lung recruitment, Yang et al. used sustained lung inflation in conventional mechanical ventilation in a more mature group of preterm infants. 70 Though we had combined both these interventions as INRECSURE, we had down rated the evidence certainty by one level due to indirectness related to the intervention and patient population. Finally, the ongoing RCT (INREC-LISA trial, NCT05711966) would provide further insights regarding the efficacy of INRECSURE.
For the sub-group of neonates born at >30 weeks' gestation, NMA also showed that rescue surfactant administration might possibly be more beneficial than using a FiO 2 threshold of 40-45%, indirectly indicating that a higher threshold may be preferred in this subgroup. This contrasts with the finding that in preterm neonates of ≤30 weeks, INSURE at FiO 2 of 40-45% was possibly associated with decreased mortality when compared to INSURE as rescue.
Very few studies have interrogated nebulized surfactant for preterm infants with RDS. A systematic review by Gaertner et al. concluded that nebulized surfactant might possibly decrease the risk of IMV in preterm neonates of <37 weeks' gestation with the CoE being low. 82 However, in preterm neonates >30 weeks' gestation, this NMA indicated that use of nebulized surfactant at a lower FiO 2 threshold of 22-30% might possibly increase the risk of IMV when compared to other lesser invasive modalities at FiO 2 22-30% and 40%. A plausible explanation could be that nebulized surfactant might not reach the alveolar space in sufficient quantity to be effective and thus, trials of nebulised surfactant might have delayed the delivery of surfactant administration through other proven modalities. One important reason we postulate for the discrepancy between our findings and that of Gaertner et al. could be that the control group included in Gaertner et al.'s metaanalysis was heterogenous and included preterm neonates who required no treatment, CPAP alone, or a more invasive surfactant administration method. The control groups in our study predominantly included preterm neonates who were diagnosed with RDS and had received surfactant through various modalities at different thresholds. More refined technologies for surfactant nebulisation are required and further clinical trials needed to confidently advise surfactant nebulisation. The optimal threshold for use of surfactant in late preterm neonates is still debated. Previously, different interpretations of evidence supporting surfactant treatment at defined FiO 2 thresholds have led to different clinical guidance, which may contribute to confusing clinical practice and possibly deleterious outcomes. More studies are needed to define the optional thresholds for surfactant therapy, tailored to the underlying pathology, disease process and means of applied respiratory support. 5 At least for late preterm and early term infants, one large RCT is currently ongoing. 83 The main strength of this NMA is that it is the only one conducted to date comprehensively evaluating the different thresholds utilized along with the modality of surfactant administration in preterm neonates with RDS. It allowed the comparison of thresholds that have not been evaluated in RCTs before. The reporting of this systematic review is in accordance with the PRISMA NMA. Further, we followed strict GRADE recommendations for assessing the CoE for the NMA. There were also some limitations. Though we took great care in assessing intransitivity addressing important factors such as gestational age and modality of surfactant administration, there still could have been intransitivity related to the type and dosage of surfactant utilized, the different CPAP levels and the wide time span across which the studies were conducted during which there have been significant advances in all areas of perinatal and neonatal care. Finally, the results of this NMA may not be generalizable to those neonates born at the threshold of viability at gestations of 22-24 weeks' as only a very few studies have included them and is an area of future research.
The results of the NMA indicate that using lesser invasive surfactant administration approaches such as INSURE and LISA with the threshold of aAO 2 < 0.36 (corresponding to an FiO 2 of 37-55%) might possibly be beneficial in preterm neonates of <30 weeks' gestation. Similarly, for the outcome of mortality, after adjusting for the effect modifier of the mode of surfactant administration, an FiO 2 40-45% was shown be associated with decreased mortality when compared to a higher threshold. Henceforth, we suggest surfactant administration in preterm neonates of ≤30 weeks' with RDS who require an FiO 2 of ≥40%. We do caution that this suggestion is based on very low to low CoE. There was insufficient evidence for the comparison of the FiO 2 thresholds of 30% vs. 40%, warranting future trials. The cost-benefit-ratio for giving surfactant at lower thresholds may need to be assessed at unit level, considering regional circumstances, which include prevalence of known aggravating risk factors for severe RDS, such as perinatal inflammation, and also treatment rates with antenatal corticosteroid. In low resource settings where blended oxygen is not always available and FiO 2 requirement cannot be adjudged, LISA, using clinical respiratory distress scoring, might possibly result in decreased risk of mortality when compared to the use of CPAP alone. Whilst the three NMAs published till date had evaluated either the modality of surfactant administration or the different FiO 2 cut-off levels, unlike this NMA none had studied these aspects wholesomely as a single intervention which could circumvent the fundamental assumption of an NMA which is intransitivity. [84][85][86] Further research into optimising surfactant treatment for RDS should focus on practical surrogates of disease severity, taking into consideration infants' gestational age, co-morbidities and predisposing factors, modality and level of respiratory support, and FiO 2 . In this context, lung ultrasound may be a very promising tool to refine the surfactant need. Also, refinement of nebulization techniques to ensure effective surfactant deposition into the alveoli is warranted. Finally, future trials and meta-analyses may include a homogenous population of ELGANs as evidence base pertaining to this sub-group is sparse.

Contributors
Drs VVR, CCR and TS conceptualized the systematic review and metaanalysis. AKPS devised the literature search strategy and was involved in the data extraction process. VVR, TB and TA verified and analyzed the data. VVR and CJW produced the initial draft. CCR, TB, TA, AKPS and TS provided further intellectual inputs and revised the initial draft. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Data sharing agreement
All data is provided in full in the results section of this paper. The relevant original source documents are cited in full in the reference section. The data can be shared with others on request via email to the corresponding author of this manuscript without any restrictions.

Declaration of interests
We declare no competing interests.